The major aim of this project is to develop new magnetic resonance (MR) "spin tagging" approaches for imaging cerebral blood flow (CBF) in humans, and to apply these approaches to study physiological and pharmacological dysfunction in psychiatric patients. The new MR approaches use classical tracer theory, but instead of using radioactive tracers they use perturbed magnetic spin states of stable isotopes. Previous work in this project: (1) identified a number of major problems that had precluded the calculation of quantitative cerebral blood flow values in humans, and developed theoretical and methodological approaches for overcoming these problems; (2) extended and revised preliminary PET validation experiments; (3) developed a new tracer kinetic model that accounts for restricted diffusion of water across the blood brain barrier; (4) developed three-dimensional arterial spin tagging approaches that can be used to study regional activation during motor activation tasks. These three-dimensional approaches solve many of the problems inherent in using two- dimensional approaches for activation studies, and also allow better spatial resolution. In the last year the 3D approaches have been used to study intrasubject and intersubject variability in regional activation during working memory cognitive tasks. The results show good intrasubject reproducibilty, but also show intersubject variation. In the next few years these experiments will be extended to study the effects of inhibitors of specific biochemical and pharmacological pathways on the cognitive activation process, and will ultimately be applied to quantitate cerebral dysfunction in psychiatric patients.